1. Field of the Invention
The present invention generally relates to microtubule stabilizing agents and methods of using thereof. Specifically, the present invention relates to coumarin compounds as microtubule stabilizing agents.
2. Description of Related Art
Microtubules, present in all eukaryotic cells, are required for normal cellular activities such as cell division, motility, anchorage, transport between cellular organelles, extracellular secretory processes, modulation of growth factor interactions with cell surface receptors and intracellular signal transduction. See Dustin, P. (1980) Sci. Am. 243:66-76. Microtubules are in dynamic equilibrium with their soluble protein subunits, xcex1 and xcex2 tubulin heterodimers.
These dynamic protein fibers are essential for cell division. During cell division, the cell must duplicate its DNA and internal components and separate them to form the two nuclei in the daughter cells. The cell then splits into two new daughter cells when these new nuclei have separated. Mitosis is the process during cell reproduction in which ordering and relocation of replicated genetic material occurs and the chromosomes are partitioned equally between two new cells. When cells enter mitosis, the microtubule network is broken down and a bipolar microtubule spindle is assembled from the centrosome. Microtubules from the spindle attach to the chromosomes and move them to the spindle poles. Dynamic instability, the rapid growing and shortening of microtubules, is responsible for the partitioning of chromosomes. These rapid dynamics are highly sensitive to antimitotic drugs. Many substances, derived from natural products, bind to tubulin or microtubules and inhibit cell proliferation by acting on spindle microtubules. Microtubules are thus, intimately involved with cell replication; if the microtubules in a tumor cell can be prevented from forming, the chromosomes cannot be partitioned, the cell cannot replicate and the tumor is unable to grow.
Various diseases and disorders are associated with microtubule assembly, disassembly, function or a combination thereof. For example, diseases and disorders associated with cell proliferation such as cancer, fungal diseases such as candida and aspergillus, cysts, neurodegenerative diseases and disorders such as Alzheimer""s disease, ALS, Pick""s and various forms of Parkinson""s, gout, malaria, atherosclerosis, restenosis, chronic inflammation, rheumatoid arthritis, psoriasis, diabetic retinopathy, and the like are associated with microtubule function.
Several agents which affect microtubule assembly, disassembly and function are known and include, vinblastine, vincristine, colchicine, allocochicine, thiocolchicine, paclitaxel (Taxol(copyright)), maytansine, rhizoxin, trityl cysteine, epothilone, discodermolide, estramustine, nocodazole, taxotere(copyright) (docetaxel) and the like. Most of these agents destabilize or disassemble microtubules which is undesirable for treating diseases and disorders relating to the abnormal destabilization or disassembly of microtubules such as Alzheimer""s disease.
However, taxol promotes the formation of microtubules and inhibits the normal dynamic reorganization of microtubules required for mitosis and cell proliferation. See Schiff, P. B., et al. (1979) Nature 277:665 and Schiff, P. B., et al. (1981) Biochemistry 20:3247. Taxol kinetically stabilizes microtubule dynamics by binding along the length of the microtubules without directly altering the cap. See Wilson, L. et al. (1985) Chemistry and Biology 2:569-573; Derry et al. (1995) Biochemistry 34(7):2203-2211. Thus, taxol has been shown to be efficacious against drug-refractory tumors such as ovarian and mammary gland tumors. See Hawkins, (1992) Oncology 6:17-23, Horwitz (1992) Trends Pharmacol. Sci. 13:134-146, and Rowinsky (1990) J. Nat""l Cancer Inst. 82:1247-1259. Unfortunately, several allergic reactions have been observed following administration of taxol. See Weiss, R. B., et al. (1990) J. Clin. Oncol. 8:1263. Additionally, cardiac arrhythmia and sinus bradycardia are associated with taxol administration in about 5% and about 40%, respectively, of patients. Furthermore, taxol is a cytotoxic agent and is toxic in large doses, over long periods of time, or both.
Therefore, a need exists for microtubule stabilizing agents which are less toxic as compared to taxol and taxol-like compounds for treating, preventing or inhibiting diseases and disorders associated with microtubule formation or function.
The present invention generally relates to coumarin compounds and derivatives thereof.
In some embodiments, the present invention provides a method of stabilizing or modulating microtubules in a subject comprising administering at least one coumarin compound or a derivative thereof to the subject. The subject may be a cell or an organism. Preferably, the subject is mammalian, more preferably, the subject is human.
In preferred embodiments, the coumarin compound is coumarin, dicoumarol, 7-hydroxycoumarin (umbelliferone), 6,7-dihydroxycoumarin (esculetin), 3,6,7 trihydroxy coumarin, warfarin, or warfarin sodium (coumadin).
In some embodiments, the present invention provides a pharmaceutical composition comprising at least one coumarin compound or a pharmaceutically acceptable salt or prodrug thereof, at least one supplementary compound and a pharmaceutically acceptable excipient. The supplementary compound may be an antineoplastic agent, an antiproliferative agent, an anti-inflammatory agent, or an anti-fungal agent. Preferably, the supplementary compound is taxol, estramustine, taxotere, vinblastine, vincristine, discodermolide, griseofulvin, or amphotericin B.
In some embodiments, the present invention provides a method of treating, preventing or inhibiting a disease or disorder associated with microtubule formation or microtubule function in a subject comprising administering to the subject a therapeutically effective amount of at least one coumarin compound or a derivative thereof. In preferred embodiments, the disease or disorder is a hyperproliferative or cystic disease. More preferably, the disease or disorder is cancer, Alzheimer""s disease, atherosclerosis, restenosis, or gout. An antineoplastic agent, an antiproliferative agent, an anti-inflammatory agent, or an anti-fungal agent may also be administered.
In some embodiments, the present invention provides a method of modulating a cell cycle of a cell comprising administering at least one coumarin compound or a derivative thereof to the cell.
In some embodiments, the present invention provides a method of treating, preventing or inhibiting cancer in a subject comprising administering to the subject a therapeutically effective amount of at least one coumarin compound or a derivative thereof and at least one antineoplastic agent. Preferably, the antineoplastic agent is taxol, estramustine, taxotere, vinblastine, vincristine, or discodermolide.
In some embodiments, the present invention provides a method of treating, preventing or inhibiting cancer in a subject comprising administering to the subject a therapeutically effective amount of at least one coumarin compound. Where only one coumarin compound is administered, the coumarin compound is not coumarin, 7-hydroxycoumarin, warfarin, or warfarin sodium.
The present invention also provides a kit for treating, preventing or inhibiting a disease or disorder associated with microtubule formation or microtubule function in a subject comprising at least one dose of at least one coumarin compound packaged together with at least one dose of an antineoplastic agent, an antiproliferative agent, an anti-inflammatory agent, or an anti-fungal agent. The kit may further comprise instructions for use, a drug delivery device such as a hypodermic needle, or both.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of this specification, illustrate several embodiments of the invention and together with the description serve to explain the principles of the invention.